Process for the quaternization of 3-diethylamino-1-cyclohexyl-1-phenyl-propanol-1 with ethyl iodide



INVENTOR. JOSEPH LOBBY AGENT lloseph Lobby, Middlesex, NJ., assigner to American Cyanamid Company, New York, N.Y., a corporation of Maine Application October 2, @1957, Serial No. 687,775 Claims. (Cl. 260-'567.6)

This invention relates to an improved process for quaternization, and more particularly, to an improved process for quaternization of S-diethylamino-l-cyclohexyl-l-phenylpropanol-l by reaction with ethyl iodide in the presence of a higher aliphatic ketone to give 3 diethylamino 1 cyclohexyl l phenyl l propanol ethiodide (hereinafter referred to by its commercial name of tridihexethyl iodide).

Tridihexethyl iodide is a valuable drug having action as a gastric secretion inhibitor and it has found wide use in the prophylaxis and therapy of peptic ulcers and other gastric disorders. In the manufacture of drugs for human therapy, high standards of purity have to be met and the manufacture to meet the required specications is often costly. Thus, it is important in any of the steps of such manufacture to keep costs as low as possible. Thus, increases in yield, purity of product, ease of mampu- 'lation and reduced labor charges are very significant.

In a step in the manufacture of tridihexethyl iodide, 3-diethylamino 1 cyclohexyl l phenyl propanol 1 is quaternized with ethyl iodide to give the nal product. This quaternization has been carried out up to now in various organic solvents, such as alcohol, acetone, `methyl ethyl ketone, ethyl acetate, or isopropyl acetate. The solvent of choice has been methyl ethyl ketone, since it Was considered to have desirable solubility and boiling point characteristics, but even with this solvent high costs of the quaternization step were encountered because of the necessity to use large amounts of ethyl iodide to cause completion of the reaction within a reasonable time. Such large excesses add considerably to the cost. In addition, the yields also left much to be desired, and the isolation of the product was complicated because the product precipitated in such a way that it was necessary to perform fractional crystallization and isolate the product in at least two crops. All these disadvantages added considerably to the cost of the drug.

I have found that if the quaternization is carried out in a saturated liquid dialkyl ketone having at least live carbon atoms, improved yields of quaternized products are obtained with much smaller excesses of ethyl iodide and the product is easily isolated in a one crop crystallization. The reduction of the excess of ethyl iodide to a reasonable amount, the obtaining of better yields and the easier manipulation all combine to'reduce the cost of the drug drastically.

It is most surprising that this change of solvents so greatly effects the commercial feasibility of the process. The effect is remarkable in that the change from a four carbon ketone, namely, methyl ethyl ketone or Z-butanone, to a five carbon ketone, such as Z-pentanone, causes a marked increase in the yield of the product and in the ease of manipulation. Since these higher aliphatic ketones boil at considerably higher temperatures, it is also most stuprising that large excesses of ethyl iodide are not needed. Whereas, ethyl iodide boils at about the same range as methyl ethyl ketone, the boiling points of these higher ketones are much above the boiling of methyl ethyl ketone. Consequently, the carrying out of a reaction at reflux temperature should cause considerably more Volatilization of the ethyl iodide and therefore, require a much larger excess in order to maintain an effective concentration of ethyl iodide with a reaction mixture.

My invention can be fully understood with reference to the accompanying figure, which is a graph of actual experimental work in which the vertical coordinate is the percent yield of quaternized product and the horizontal coordinate is the excess ethyl iodide used. In all cases, except 3octanone which was run at 12S-130 C., the reaction was run at the reiiux temperature of the solvent indicated, for 7 hours. There is a striking change in the yields obtained, at low excesses of ethyl iodide between Z-butanone or methyl ethyl ketone and the next higher ketone Z-pentanone or methyl propyl ketone, which are the lines labelled 1 and 3, respectively, Line 2 is the solvent of choice 4-methy1-2-pentanone or methyl isobutyl ketone. In addition, the graph shows the position of points for a number of other solvents used in the prior art (such as acetone 5 or isopropyl acetate 6). Another of those usable in the present invention (3-octanone) 4. Also shown is an unusable cyclic ketone (cyclohexanone) 7.

Examples of the liquid dialkyl ketones having at least Y tive carbon atoms which may be used are methyl isobutyl ketone, methyl propyl ketone, methyl butyl ketone,

ethyl amyl ketone, and the like.

Although various of the higher boiling dialkyl ketones of live or more total carbon atoms may be used, it is preferred to use methyl isobutyl ketone. Itis necessary, of course, that the ketone have solubility characteristics such that the product may be isolated easily.

In the practice of my invention, the 3diethylaminol cyclohexyl-l-phenylpropanol-l is heated with the ethyl iodide in the ketone using'at least about 1.5 parts of the ketone per part of the 3-diethylamino-l-cyclohexyl-lphenylpropanol-l. Preferably about 2.8 parts or more are used, i.e., an amount suiicient to give a complete solution at the reaction temperature. In the process, the larger excesses (up to 260% or more) of the ethyl iodide necessary when a solvent such as methylA ethyl ketone is used are not necessary. However, an excess of ethyl iodide (up to about 50-60%) is desirable for best results, using the `longer chain ketone. With an excess of the order of about 60%, product yields range about of theoretical. This is an extremelyv important advantage of the process of the invention because of the high cost of ethyl iodide (it has averaged $3.30 lb. for 5 years). Increasing the excess to a higher figure is not necessary, since there is no appreciable further yield improvement.

Although it is not necessary to heat lthe reaction mixture to give satisfactory yields, since yields of the order of 88% are possible at room convenient and practical from the standpoint of time to heat the mixture at temperatures somewhat about It is often convenient to reflux the mixture whereby the reaction mixture is heated at the boiling point of the ketone, for example, with methyl isobutyl ketone at about 10S-110 C., good results are then obtained in a much shorter time. However, temperatures in excess of about C. are not desirable. The time required for the completion of the reaction will necessarily depend on the temperature used.

In such quaternization reactions the presence of water often influences the reaction to a certain degree. This is more true at the higher temperatures (equal yields are obtained at room temperature even when Water is present). But it is an advantage of the process of the invention that the complete absence of water is not critical.

temperature, it is more In carrying out the process by the preferred method, it is often convenient to remove foreign matter from the reaction solution prior to heating by iiltration using a lter aid. The clarified mixture is then heated at the reflux temperature (provided the reflux temperature of the ketone is not 4above about 150) and after the reaction is complete, the reaction mixture is cooled to allow the product to crystallize completely, and the product is isolated by ordinary methods.

The invention is further illustrated by the examples which follow.

EXAMPLE 1 Preparation of trdz'hexethyl iodide To 1320 parts of methyl isobutyl ketone is added 570 parts of S-dethyl-amino-l-cyclohexyl-l-phenylpropanol- 1 (2 moles) and the mixture is stirred until solution is complete. Then 500 parts (3.2 moles or 60% excess) of ethyl iodide `are added. After ltration, the filtrate is diluted with an additional 300 parts of methyl isobutyl ketone and the solution is then heated at the redux ternperature (S-110 C.) for 9 hours. After cooling to 0 C., the precipitated solid material is removed by filtration, washed with isopropyl acetate and dried. Approximately 777 parts of product is obtained or a yield of 88.6% based on Aas-is starting material or 92.5% based on real starting material.

EXAMPLE 2 One part of 3-diethylamino-l-cyclohexyl-l-phenylpropanol-l is added to 2.8 parts of the ketone shown in the table. The designated amount of ethyl iodide is added and the mixture is heated at the reflux temperature. After cooling the mixture, the product is isolated by ltration. The following table, from which parts of the data for the ligure were extracted, shows the excess of ethyl iodide added, reflux period and temperature, and yield of quaternized product.

Per- Ketone used (or cent Percent Run solvent) excess Reaction Condition Yield oi Ethyl Product Iodide 1- Methyl propyl ketone 60 Reflux, 7 hrs 88.1

(Z-pentanone). 2 do 260 -do S8. 3 3 .do 60 2S days at room 87. 6

temperature. 4.,-.. Ethyl amy] ketone 60 7 hrs., 12S-130 C- 90. 9

(Zi-octanonc). 5..--- Acetone Reflux, 24 hrs 68. 0 6-.-... Isopropyl acetate- 260 Redux, 7 hrs 49. 7 7..-.. Oyclohexanone 28 days at room 0. 0

temperature. 8 do 60 Redux, 7 hrs 0. D

I claim:

1. In the process of quaternizing 3-diethylamino-lcyclohexyl-l-phenylpropanol-l with ethyl iodide comprising bringing the said ethyl iodide into reactive contact with the said diethylamino cyclohexyl phenylpropanol, the improvement which comprises carrying out the reaction in at least 1.5 parts of a solvent, the said solvent consisting essentially of saturated liquid dialkyl ketones having a minimum of 5 carbon atoms and a maximum of carbon atoms, per part of said diethylaminocyclohexylphenylpropanol using no larger excess of ethyl iodide than over stoichiometrical.

2. The process of claim 1 in which the said ketone is methyl isobutyl ketone.

3. The process of claim 2 in which the ketone usage is about 2.8 parts of said ketone per part of said diethylaminocyclohexylphenylpropanol. l

4. The process of claim 3 in which the reaction is carried out at the boiling point of said ketone.Y

5. 'Ihe process of claim 4 in which the said ethyl iodide is present in less than 100% excess over the stoichiometrical amount.

Percent Percent Run Solvent Excess Reaction Reaction Temp., C. Yield of No. Ethyl Time Product Iodlde 1 Methyl ethyl ketone 10 7hrs 26.1 2- dn 100 7hrs 74.7 a do 260 7 hrs s4. 5 4 do so 24hrs.-- 87.6 5 Methyl isobutyl ketone--. 10 7 hrs S5. 2 d 30 7hrs- 88.5

50 7hrs 90 60 7hrs.. 91.2 so 7nrs 90.8 260 7nrs 90.8 so 7r1rs 95 77.1 en 7nrs so 56.1 6o 2s days. 88.2

References Cited' in the file of this patent EXAMPLE 3 55 FOREIGN PATENTS The procedure of Example 2 is followed using various 609,454 'Great Britain sept 30, 1948 other solvents with the results being shown in the follow- 627,139 Great Britain july 29s 1949 ing table, from which the rest of the data in the gure were extracte 60 OTHER REFERENCES D. W. Adamson: I. Chem. Soc., 1949, Supp. Issue, No. 1, S, 144-55.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIN Pai-ems NO 2,913,494 November 17, 1959 lJorsepo Lobby It is hereby certified that error appears in the printed specification of' the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Golumn w line 26, claim l, for "of .carbon latomsH read om of 8 carbon etoms,

Signed and sealed this '7th day of June 1960.

(SEAL) Attest:

KARL H.- `MCLTNE Attesting Ocer ROBERT C. WATSON Commissioner of Patents 

1. IN THE PROCESS OF QUATERNIZING 3-DIETHYLAMINO-1CYCLOHEXY-1-PHENYLPROPANOL-1 WITH ETHYL IODIDE CONPRISING BRINGING THE SAID ETHYL IODIDEIINTO REACTIVE CONTACT WITH THE SAID DIETHYLAMINO CYCLOHEXYL PHENYLPROPANOL, THE IMPROVEMENT WHICH COMPRISES CARRYING OUT THE REACTION IN AT LEAST 1.5 PARTS OF A SOLVENTM THE SAID SOLVENT CONSISTING ESSENTAILLY OF SATURATED LIQUID DIALKYL KETONES HAVING A MINIMUM OF 5 CARBON ATOMS AND A MAXIMUM OF CARBON ATOMS, PER PART OF SAID DIETHYLAMINOCYCLOHEXYLPHENYLPROPANOL USING NO LARGER EXCESS OF ETHYL IODIDE THAN 100% OVER STOICHIOMETRICAL. 